The present invention generally relates to dermal filler compositions, and more specifically relates to injectable dermal filler compositions that are effective for treatment of fine lines in skin.
Skin aging is a progressive phenomenon, occurs over time and can be affected by lifestyle factors, such as alcohol consumption, tobacco and sun exposure. Aging of the facial skin can be characterized by atrophy, slackening, and fattening. Atrophy corresponds to a massive reduction of the thickness of skin tissue. Slackening of the subcutaneous tissues leads to an excess of skin and ptosis and leads to the appearance of drooping cheeks and eye lids. Fattening refers to an increase in excess weight by swelling of the bottom of the face and neck. These changes are typically associated with dryness, loss of elasticity, and rough texture.
Hyaluronic acid (HA), also known as hyaluronan, is a non-sulfated glycosaminoglycan that is distributed widely throughout the human body in connective, epithelial, and neural tissues. Hyaluronic acid is abundant in the different layers of the skin, where it has multiple functions such as, e.g., to ensure good hydration, to assist in the organization of the extracellular matrix, to act as a filler material; and to participate in tissue repair mechanisms. However, with age, the quantity of hyaluronic acid, collagen, elastin, and other matrix polymers present in the skin decreases. For example, repeated exposed to ultra violet light, e.g., from the sun, causes dermal cells to both decrease their production of hyaluronan as well as increase the rate of its degradation. This loss of materials results in various skin conditions such as, e.g., wrinkling, hollowness, loss of moisture and other undesirable conditions that contribute to the appearance of aging.
Injectable dermal fillers have been successfully used in treating the aging skin. The fillers can replace lost endogenous matrix polymers, or enhance/facilitate the function of existing matrix polymers, in order to treat these skin conditions. Hyaluronic acid-based dermal fillers have become increasingly popular, as hyaluronic acid is a substance naturally found throughout the human body. These fillers are generally well tolerated, nonpermanent, and a fairly low risk treatment for a wide variety of skin conditions.
Tyndall effect is an adverse event occurring in some patients administered with hyaluronic acid (HA)-based dermal fillers. Tyndall effect is characterized by the appearance of a blue discoloration at the skin site where a dermal filler had been injected, which represents visible hyaluronic acid seen through the translucent epidermis. Clinical reports suggest that filler administration technique and skin properties can influence the manifestation of this adverse event. Fillers with high stiffness and elasticity are successfully used to correct areas on the face like nasolabial folds, cheeks, and chin without any fear of facial discoloration, as the materials are injected in the mid and deep dermis regions. However, when these filler materials are used to correct superficial, fine line wrinkles, for example, tear trough, glabellar lines periorbital lines, smile lines, or forehead, or mistakenly applied too superficially in the upper regions of the dermis, a bluish discoloration of the skin is often observed. This phenomenon, which is thought to be the result of Tyndall effect, leaves a semi-permanent discoloration of the application sites, and sometimes disappears only after the administration of hyaluronidase to degrade the filler material. Consequently, Tyndall effect is more common in patients treated for superficial fine line wrinkles. Prolonged manifestation of Tyndall effect, typically for several months as long as the gel lasts in the skin, is a cause of major concern among patients.
HA-based dermal filler gels have been specifically formulated to treat “fine line” wrinkles found around the tear trough, forehead, periobital, glabellar lines, etc. Commercially available HA “fine line” gels include Juvéderm Refine (G′˜67 Pa; G″/G′˜0.59, HA concentration 18 mg/ml), Belotero Soft (G′˜28 Pa; G″/G′˜1.1, HA concentration 20 mg/ml), Emervel Touch (G′˜56 Pa; G″/G′˜0.64, HA concentration 20 mg/ml), Stylage S (G′˜192 Pa; G″/G′˜0.20, HA concentration 16 mg/ml), Teosyal First Lines (G′ 59 Pa; G″/G′˜0.53, HA concentration 20 mg/ml), Restylane Touch (G′˜489 Pa; G″/G′˜0.24, HA concentration 18 mg/ml). Though these gels are formulated to have low elastic moduli, for example, by lightly crosslinking the linear HA chains with a small amount of crosslinker and/or by reducing the final HA concentration of these gels, most of the commercially available “fine line” gels still show Tyndall effect in some patients, especially when injected superficially, for example, at a depth of less than about one mm.
Collagen-based gels can be employed in the treatment of superficial wrinkles and does not appear to cause Tyndall effect. Collagen based gels are not highly favored as they have relatively poor duration in the skin and require pre-testing in individuals. Radiesse® (calcium hydroxylapatite) is a subdermal, injectable implant, whose principal component is synthetic calcium hydroxylapatite, not hyaluronic acid. Unlike hyaluronic acid-based dermal fillers, calcium hydroxylapatite is not transparent, and thus avoids the complication of the Tyndall effect. However, if placed too superficially, this filler can be seen as a white substance immediately beneath the skin. Furthermore, compared to hyaluronic acid based fillers, Radiesse® requires a larger needle for injection and is not typically recommended for use in the eye area.
It would be desirable to provide an injectable hyaluronic acid-based dermal filler that does not exhibit the bluish discoloration attributed to Tyndall effect, even when injected superficially.